P616: LONG-TERM FOLLOW-UP UPDATE AND MULTIVARIABLE ANALYSES OF FACTORS ASSOCIATED WITH DURATION OF RESPONSE AFTER CD19 CAR T-CELL THERAPY FOR RELAPSED/REFRACTORY CLL
Authors: Emily Liang, Alexandre Hirayama, Erik Kimble, Andrew Portuguese, Aya Albittar, Aude Chapuis, Mazyar Shadman, Brian Till, Ryan Cassaday, Filippo Milano, Hans-Peter Kiem, Camesron Turtle, David Maloney, Jordan Gauthier
Journal: HemaSphere (2023)

Topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical Background: CD19-targeted chimeric antigen receptor-modified (CD19 CAR) T-cell therapy is transforming the treatment of patients with relapsed/refractory (R/R) B cell malignancies. We have reported high efficacy in patients (pts) with high-risk R/R chronic lymphocytic leukemia (CLL) treated on a phase I/II clinical trial of CD19 CAR T cells, but with limited follow-up (NCT01865617; Turtle, JCO 2017). Aims: We report comprehensive analyses of factors associated with duration of response (DOR) with a 68-month median follow-up. Methods: We included 49 pts with R/R CLL and/or Richter’s transformation (n = 10) treated on a phase I/II clinical trial of defined-composition CD19 CAR T-cell therapy (1:1 ratio of CD8+:CD4+ CAR T cells). Patients received CAR T cells without (n = 30; stopped prior to lymphodepletion [LD]) or with concurrent ibrutinib (n = 19; started ≥2 weeks prior to leukapheresis; Gauthier, Blood 2019). Response was defined as complete or partial response (PR) by investigator-assessed 2018 iwCLL criteria at day+28. Measurable residual disease (MRD) in bone marrow (BM) was evaluated by multiparameter flow cytometry (MFC) and IGH next-generation sequencing (NGS; clonoSEQ assay). CAR T-cell enumeration was assessed by MFC. Serum cytokine concentrations (20 analytes) were measured by Luminex assay. Univariate associations between patient, disease, CAR T-cell manufacturing, treatment-related variables (50+ predictors), and MRD-negative CR by MFC or DOR were estimated using logistic or Cox regression, respectively. Results: Median age was 61 years (IQR, 55-67). Forty-six pts (94%) had complex karyotype and/or 17p deletion; 47 (96%) were ibrutinib-refractory or intolerant. In the response-evaluable cohort (n = 47), median follow-up was 68.3 months (IQR, 54.3-81.6). Overall and CR rates at day+28 by iwCLL criteria were 70% and 17%, respectively, and the median DOR was 21.3 months (95% CI, 9.82-not reached [NR]). We observed MRD negativity at day+28 by MFC in 27/36 (75%). In pts with MRD negativity by MFC and available data, 18/25 (72%) were MRD-negative by NGS. In NGS MRD-negative responders, the median DOR was 55.9 months (95% CI, 38.6-NR). DOR stratified by MRD status is shown in Figure 1A-B. In all evaluable patients, the 5-year OS and PFS were 35.6% (95% CI, 24.0%-52.5%) and 21.5% (95% CI, 12.0%-38.5%), respectively. In univariable logistic regression, higher peak CD8+ (OR = 4.97, 95% CI, 2.10-16.6, p = 0.002) and CD4+ CAR T-cell expansion (OR = 5.11, 95% CI, 2.05-17.1, p = 0.002), and lower peak MIP-1β (OR = 0.21, 95% CI, 0.05-0.81, p = 0.032) were associated with higher odds of day+28 MRD negativity by MFC. In univariable Cox regression, day+28 MRD negativity by MFC (HR = 0.03, 95% CI, 0.00-0.14, p < 0.001), day+28 MRD negativity by NGS (HR = 0.21, 95% CI, 0.07-0.61, p = 0.004), higher peak CD8+ CAR T-cell expansion (HR = 0.54, 95% CI, 0.33-0.89, p = 0.016), CAR T-cell persistence (HR = 0.64, 95% CI, 0.47-0.88, p = 0.005), and lower peak MIP-1β (HR = 2.56, 95% CI, 0.98-6.72, p = 0.056) were associated with longer DOR (Figure 1C-D). Higher peak MIP-1β levels remained associated with shorter DOR (HR = 4.00, 95% CI, 1.04-15.4, p = 0.044) in a multivariable model including pre-LD CLL cells in BM, tumor cross-sectional area, concurrent ibrutinib, peak CD8+ CAR T-cell expansion, and day+28 MRD by MFC. Summary/Conclusion: CD19 CAR T-cell therapy achieved durable remissions in high-risk R/R CLL pts. Day+28 MRD positivity by MFC or NGS were strong predictors of shorter DOR. Higher in vivo CAR T-cell peak expansion and longer CAR T-cell persistence were associated with longer DOR. Lower peak levels of serum MIP-1β, a cytokine known to be produced by CLL cells upon BCR activation and previously described as a poor prognostic factor, were strongly and independently associated with DOR.Keywords: Measurable residual disease, Chronic lymphocytic leukemia, Clinical trial, CAR-T